Whenever a medical device is used in a surgical setting, a risk of infection is created. The risk of infection dramatically increases for invasive or implantable medical devices, such as intravenous catheters, arterial grafts, intrathecal or intracerebral shunts and prosthetic devices, which create a portal of entry for pathogens while in intimate contact with body tissues and fluids. The occurrence of surgical site infections is often associated with bacteria that colonize on the medical device. For example, during a surgical procedure, bacteria from the surrounding atmosphere may enter the surgical site and attach to the medical device. Bacteria can use the implanted medical device as a pathway to surrounding tissue. Such bacterial colonization on the medical device may lead to infection and morbidity and mortality to the patient.
A number of methods for reducing the risk of infection associated with invasive or implantable medical devices have been developed that incorporate antimicrobial metals or metal salts into the medical devices. Such devices desirably provide effective levels of the antimicrobial metal while the device is being used.
For many years silver and silver salts have been used as antimicrobial agents in medical applications. Such medical applications include the use of aqueous silver nitrate solutions to prevent eye infection in newborn babies. Silver salts have also been used to prevent and control infection such as conjunctivitis, urethritis, and vaginitis.
Additionally, silver and silver salts have been used as antimicrobial agents in conjunction with medical devices, such as catheters, cannulae, and stents. Typically, the silver or silver salt is deposited directly onto the surface of the medical device via conventional coating techniques, such as vapor coating, sputter coating, or ion beam coating.
For example, WO 2004054503A2 and U.S. Pat. No. 6,878,757 to Roby describe antimicrobial coatings applicable to sutures where the coating comprises (i) mixtures of caprolactone copolymers and silver stearate, and (ii) mixtures of copolymers of epsilon-caprolactone, bioabsorbable monomer and sodium stearoyl lactylate or the silver salt of stearoyl lactylate, respectively. The silver salt in both of these references remains in a salt form in the copolymer matrix, and silver ions are released into a target environment from the coating by solubilization of the silver salt in the target environment. In turn, the solubility of the silver salt is a function of the nature of environment where it is delivered, and factors such as counter-ion concentration and ionic strength of the target environment.
U.S. Pat. No. 6,881,766 to Hain describes sutures fabricated from and/or coated with compositions including water-soluble glass. The water-soluble glass optionally includes a therapeutic agent, e.g., silver, to promote wound repair. The silver in this case may be incorporated in the form of an inorganic silver salt such as silver oxide, silver nitrate or silver orthophosphate. Similar to the reference described above, the release of the silver ions into the target environment may be dependent upon the solubility of the silver salt in the target environment.
Other metals, such as zinc, copper, magnesium and cerium, have also been found to possess antimicrobial properties, both alone and in combination with silver, some of which exhibited synergistic benefits of their combinations. These and other metals have been shown to provide antimicrobial behavior even in minute quantities.
Other methods of coating antimicrobial metals or metal salts onto a substrate involve deposition or electro-deposition of the metal or metal salt from solution. Additional techniques for incorporating metal into a medical device include dipping, spraying or brushing a liquid solution of the metal or metal salt onto a polymer, for example, in pellet form, prior to processing the medical device. Alternatively, a solid form of the metal or metal salt can be mixed with a finely divided or liquefied polymeric resin, which is then molded into the article. Also, the metal or metal salt can be mixed with monomers of the material prior to polymerization.
However, problems associated with medical devices having metal or metal salts deposited thereon by conventional incorporation techniques include poor adhesion of the metal or metal salt on the medical device, and lack of uniformity in the concentration of the metal or metal salt throughout the coating. Also, it is believed that deposition or electro-deposition of the antimicrobial metal onto a medical device produces coatings that do not release the metal from the coating easily, and therefore require direct contact with microbes in the tissue to have an antimicrobial effect.
U.S. Pat. No. 6,153,210 to Roberts et al. discloses polymeric microparticles containing metal ions, preferably silver ions, for control of periodontal disease. The microparticles can be made from poly(lactide-co-glycolide) (PLGA) having MW of about 12,000 Daltons, with which the metal ions are mixed or complexed. However, Roberts et al. are silent as to the ion exchange capacity of their polymers, and as to PLGA having MW of less than about 10,000 Daltons.
Therefore, there is a need to provide an antimicrobial composition where the release mechanism of metal ions into the target environment is not dependent upon solubilization in the target environment. More particularly, there is a need for an antimicrobial composition that exhibits immediate activity upon contact with fluids in the human body. Additionally, it is desirable to have an antimicrobial composition that adheres well to medical devices, as well as antimicrobial medical devices having a uniform distribution of metal or metal salts throughout.